Survival function of 4 treatment groups stratified by age at
current episode. Kaplan-Meier tests of survival function were
significant for subjects aged 60 to 69 years
(log-rank=25.91; df=3;
P=.001) and subjects 70 years or older
(log-rank=9.05; df=3;
P=.03). Pairwise contrasts within each age
stratum were not performed due to small sample sizes. IPT indicates
interpersonal psychotherapy.

Old Age Depression Interest Group (OADIG). How long
should the elderly take antidepressants? a double-blind,
placebo-controlled study of continuation/prophylaxis therapy with
dothiepin. Br J Psychiatry.1993;162:175-182.

Context Elderly patients with major depression are at high
risk for recurrence, increased mortality, and chronic disability.

Objective To determine the efficacy of maintenance nortriptyline
hydrochloride and interpersonal psychotherapy (IPT) in preventing
recurrence of major depressive episodes in patients older than 59 years.

Patients Of a total of 187 patients with recurrent nonpsychotic
unipolar major depression (average age, 67 years; one third aged ≥70
years) recruited through clinical referral and media announcements, 107
were fully recovered after open acute and treatment continuation with
nortriptyline and IPT. These patients were randomly assigned to 1 of 4
maintenance therapy conditions.

Results The time to recurrence of a major depressive episode for
all 3 active treatments was significantly better than for placebo.
Recurrence rates over 3 years were as follows: nortriptyline and IPT,
20% (95% confidence interval [CI], 4%-36%); nortriptyline and
medication clinic visits, 43% (95% CI, 25%-61%); IPT and placebo,
64% (95% CI, 45%-83%); and placebo and medication clinic visits,
90% (95% CI, 79%-100%). Combined treatment with nortriptyline and
IPT was superior to IPT and placebo and showed a trend to superior
efficacy over nortriptyline monotherapy (Wald
χ2=3.56; P=.06).
Subjects aged 70 years and older had a higher and more rapid rate of
recurrence than those aged 60 to 69 years.

Conclusion In geriatric patients with recurrent major depression,
maintenance treatment with nortriptyline or IPT is superior to placebo
in preventing or delaying recurrence. Combined treatment using both
appears to be the optimal clinical strategy in preserving
recovery.

Old-age
depression is widespread, affecting at least 1 in 6 patients in general
medical practice and an even higher percentage in hospitals and nursing
homes.1- 3 Depression, especially in later life, has serious
health consequences, including increased health care
costs,4 increased mortality related to suicide5
and medical illness,6,7 and amplification of disability
associated with medical and cognitive disorders.8 A recent study by the World Health Organization concluded that unipolar major
depression and suicide accounted for 5.1% of the total global burden
of disease in 1990, making depression the fourth most important cause
of global burden of disability.9 The study also showed that the significance of illness burden attributable to depression increases
with age weighting and is projected to grow further by the year 2020,
based on demographic shifts toward a greater proportion of aging adults
in the population, especially of the very old.

Depression in old age can be effectively treated during acute and
continuation therapy over 6 to 12 months.10,11 However, to
meet the public health challenges posed by old-age depression for the
next 20 years, one of the major priorities for intervention research is
to find maintenance treatments with long-term efficacy in preventing
recurrence. The goal of this research has been to assess the efficacy
of antidepressant medication (nortriptyline hydrochloride) and of
interpersonal psychotherapy (IPT)12 in helping elderly
depressed patients to maintain recovery and to prevent or delay
recurrence. The long-term prognosis for geriatric depression has
generally been considered mixed, with only one quarter to one third of
patients robustly well at 1 to 3 years of follow-up in naturalistic
studies.13,14 Patients older than 70 years appear to have a
particularly brittle response that is prone to relapse and present
special challenges for long-term clinical management.15
Furthermore, other studies have indicated that old age at first onset
of illness increases the risk of recurrence and that the shorter the
symptom-free interval, the greater the risk for
recurrence.16- 18 Hence, once effectively treated, how can
elderly patients with major depression (especially recurrent
depression) be kept well? That has been the primary question addressed
by the current study.

Until now, there have been no studies of maintenance psychotherapy in
the depressed elderly, or of combined treatment with medication and
psychotherapy. However, we think it important that
psychotherapeutic approaches be developed and assessed in conjunction
with pharmacotherapy in maintenance research, especially for
depressed older patients who cannot or will not take
antidepressant medication, as well as for patients for whom
psychosocial factors such as bereavement, role transition, and
interpersonal conflict are clinically significant.

This study builds on the work of Frank et al,19 who
demonstrated the efficacy of the tricyclic antidepressant (TCA)
imipramine hydrochloride and of IPT in preventing or delaying
recurrences of major depression in midlife patients. We hypothesized
that recurrence rates would be significantly higher in the placebo
condition than in any of the active treatment conditions, that time to
recurrence would be shorter in the placebo condition than in any of the
active treatment conditions, and that combined treatment with
nortriptyline and IPT would be superior to either treatment alone in
preventing recurrences.

METHODS

Study Site and Study Population

The study was conducted at a university-based geropsychiatric
research clinic. Over a 7-year period, we recruited 187 elderly
patients with recurrent, nonpsychotic, nondysthymic, unipolar major
depression, of whom 180 actually began treatment
(Table 1).
Patients were required to be 60 years
or older and to meet expert clinical judgment and research
diagnostic criteria, as established by structured interview with
the Schedule for Affective Disorders and Schizophrenia-Lifetime
Version,20 for recurrent non-psychotic unipolar major
depression. Patients were also required to be at least in their second
lifetime episode, with an interepisode wellness interval of no longer
than 3 years, a Hamilton Depression Rating Scale (17-item) score of 17
or greater,21 and a Folstein Mini-Mental State
Examination score of 27 or greater.22 All subjects provided written informed consent.

We screened 687 subjects to yield the study group of 187. Of the
500 subjects excluded, 119 had single episodes of major depression, 63
had interepisode wellness intervals longer than 3 years, 43 presented
medical contraindications to the use of nortriptyline, and 23 had
dysthymia as well as major depression. Additional reasons for exclusion
included: 12 who failed to meet study age criteria, 24 with delusional
depression, and 135 with other psychiatric diagnoses. Excluded patients
were offered treatment at the Benedum Geriatric Center at the
University of Pittsburgh Medical Center, Pittsburgh, Pa. Reliable data
concerning treatment history were not generally available.
Of the patients who began active treatment, 48.7% were
clinically referred, 42.6% were recruited through the media
and community presentations, and 8.7% learned of the study by word of
mouth.23

Study Design

Patients received open treatment initially using a combination
of nortriptyline hydrochloride (with plasma steady-state levels of
80-120 ng/mL) and weekly IPT to achieve a remission of depressive
symptoms, as defined by a score of 10 or less on the 17-item Hamilton
Depression Rating Scale. During acute treatment 92 (51.1%) of 180
patients received adjunctive pharmacotherapy with lithium or
perphenazine, as reported elsewhere.11 Twenty-eight
(18.4%) of 159 patients who completed acute and continuation treatment
failed to remit at all or to show stable remission and were judged to
be resistant to treatment.11 Following successful acute treatment, patients entered a 16-week period of continuation therapy to
ensure stability of remission and full recovery. Continuation treatment
consisted of combined nortriptyline and IPT, using the same dosage of
nortriptyline as used during the acute phase, but with the frequency of
IPT reduced to every other week. Patients whose remissions were stable
for 16 weeks were then randomly assigned to 1 of 4 maintenance therapy
conditions: (1) medication clinic with nortriptyline hydrochloride
(80-120 ng/mL); (2) medication clinic with placebo; (3) monthly
maintenance IPT and nortriptyline; or (4) monthly maintenance IPT with
placebo. Nortriptyline and placebo tablets were identical in size (9 mm
in diameter), weight (250 mg), and appearance. For patients
randomly assigned to a maintenance placebo condition, nortriptyline was
slowly discontinued over 6 weeks under double-blind conditions.
Patients remained in maintenance therapy for 3 years or until
recurrence of a major depressive episode, whichever occurred first.

The randomization schedule was generated by the project statistician at
the beginning of the trial and given to the research pharmacist. The
individual randomization was stratified by therapist and blocked in
units of 4 subjects. The method to generate the allocation schedule was
a Fortran program using the DIGITAL VAX/VMS operating system
randomization subroutine based on the permutation procedure described
by Fleiss.24 Only the pharmacist
and the open monitoring
committee (J.M.P. and C.C.) had knowledge of randomized assignment to
nortriptyline or placebo. The treatment team, outcome assessors, and
data analyst were blind to treatment assignment.

As shown in Figure 1, 124
(68%) of 180 treated patients recovered and were randomly assigned to
a maintenance therapy condition. Of these, 13 relapsed during the
transition to maintenance (that is, during double-blind discontinuation
of nortriptyline and substitution of placebo) and 107 fully recovered
patients began maintenance treatment.

We chose nortriptyline for 2 reasons. First, our review of the
literature on the treatment of geriatric depression concluded that the
available database supported the efficacy of nortriptyline as the
best antidepressant available.25
Second, our pilot work supported nortriptyline's favorable adverse
effect profile in the elderly. Similarly, we chose IPT because, as
originally developed by Klerman et al,12 it included
specific foci on grief, interpersonal disputes, and role transitions,
problems that were prevalent in our patient population and relevant to
the onset of depression.

Each patient was seen monthly during maintenance treatment by the same
2 clinicians who had treated him/her during acute and continuation
treatment, a nonphysician clinician and a coinvestigator psychiatrist,
both blind to pharmacotherapy assignment. Patients in the medication
clinic condition were seen for 30-minute visits; they received no
specific psychotherapy but were queried about their symptoms and any
possible adverse effects. Blood samples for nortriptyline were drawn at
each clinic visit. Plasma nortriptyline levels were determined by
high-performance liquid chromatography.26 All visits, both medication clinic and psychotherapy, included orthostatic blood
pressure and pulse determinations, weight, and clinical ratings
(Hamilton Depression Rating Scale, Beck Depression Inventory, Global
Assessment Scale, and Asberg Side-Effect Rating
Scale).21,27- 29 These data were reviewed by a nonblind
monitoring committee (J.M.P. and C.C.), which adjusted the dosage of
nortriptyline hydrochloride to ensure a steady-state level of 80 to 120
ng/mL.

Patients assigned to monthly maintenance IPT were seen during
50-minute sessions by experienced clinicians (2 with master's degrees
in social work, 1 with a master's degree in education counseling, and
1 with a doctorate in clinical psychology). Psychotherapists were
trained to research levels of proficiency and received ongoing
supervision by 4 of the investigators (E.F., S.D.I., C.C., and M.D.M.).
These same clinicians also provided medication-clinic management to
patients randomly assigned to medication clinic. All medication clinic
and monthly maintenance IPT sessions were audiotaped for rating of
elements specific to IPT and to medication clinic to ensure treatment
integrity and compliance with manual-based treatment delivery
procedures.30 We monitored
compliance with pharmacotherapy
via education of patient and family members, pharmacy pill counts,
weekly reminders and checks, and by examination of nortriptyline
level-to-dose ratios over time.31

Recurrence of a major depressive episode, as defined by research
diagnostic criteria, was determined by structured psychiatric interview
performed by a research nurse and independent clinical confirmation by
a senior psychiatrist. There were no protocol deviations from the study
as planned.

Statistical Methods

We used Kaplan-Meier survival analysis with log-rank statistics to test
for differences in the survival function of the maintenance treatment
groups, followed by post-hoc pairwise comparisons. For pairwise
comparisons we used a Cox proportional hazards model with 3 dummy
variables representing the 4 treatment groups that allowed comparison
of the hazard functions. A Cox model also allowed us to test and
control for the effects of possible covariates such as age at study
entry, number of prior episodes of major depression, duration of acute
therapy, social support (Interpersonal Support Evaluation
List32), and chronic medical
burden (Cumulative Illness
Rating Scale for Geriatrics33). The proportionality
assumption of the Cox model was tested using the placebo group as the
reference. The fit of the model was also judged using Martingale
residuals.

RESULTS

A total of 107 patients who had fully recovered began
maintenance treatment. Analysis of recurrence was performed on data
from these subjects (Figure 2 and
Table 2). Because 5 subjects were
still active at the time of the final outcome analysis (3
in nortriptyline and IPT and 2 in nortriptyline and medication clinic),Table 2
presents the outcome data with the active subjects censored.
These 5 patients had all completed at least 2 years of maintenance
treatment without recurrence.

The survival analysis showed a highly significant effect for active
treatment over placebo in preventing recurrence of major depressive
episodes (log rank=34.31; P<.001). The best
outcome was observed in patients assigned to the combined treatment
condition, with 80% remaining depression-free. A Cox proportional
hazards model using 3 dummy variables representing the 4 treatment
groups was then fit with age group as a covariate. The proportionality
assumption was tested and met. On pairwise analysis, each of the active
treatment conditions was significantly better than placebo in
preventing recurrence: nortriptyline and IPT (P<.001);
medication clinic with nortriptyline (P<.001); and IPT with
placebo (P=.03). Combined treatment was
superior to IPT and placebo (P=.003) and
showed a trend to superior efficacy over medication clinic with
nortriptyline (Wald χ2=3.56;
P=.06). Nortriptyline and medication clinic vs
IPT and placebo did not differ (P=.16). Most
recurrences took place in the first year of treatment
(Table 3). Of 17 recurrences in patients taking
maintenance nortriptyline, 9 were associated with noncompliance as
inferred from variability in level-to-dose ratios.30 Six of 17 recurrences in a nortriptyline condition were not associated with
pharmacological indices of noncompliance. In the remaining 2 cases,
data were incomplete. The proportion of patients in combined treatment
was the same in noncompliant (3/9) and compliant (2/6) patients.

We examined 3-year outcomes in patients aged 60 to 69 years
(n=69) and in those 70 years or older
(n=38) in a survival analysis using the Kaplan-Meier
method. As shown in Figure 3 and
Table 4, older age was associated
with a higher and more rapid rate of recurrence during the first year
of maintenance with nortriptyline and medication clinic, IPT and
placebo, and placebo and medication clinic conditions. Only combined
treatment with nortriptyline and IPT effectively prevented recurrence
during the first year of maintenance therapy in subjects 70 years or
older. In subjects aged 60 to 69 years, each of the monotherapies and
combined therapy were equally effective in preventing recurrence during
the first year.

Several clinical variables have been associated with higher
liability to recurrence in naturalistic studies of late-life
depression. These include older age at index
episode, number of previous episodes, extent of
chronic medical burden and associated disability, time to remission,
and social support. Higher age at study entry was associated with a
greater liability to recurrence (P=.05), but
none of the other measures were significant covariates in a Cox
proportional hazards model. There was also no relationship between
referral source and outcome, with similar recurrence rates observed in
patients who were clinically referred and self-referred.

Attrition for reasons other than recurrence of depression was low
during maintenance treatment. Six (10%) of 58 subjects in a
maintenance nortriptyline condition were dropped because of
intercurrent medical problems contraindicating the further use of
nortriptyline, compared with 0 (0%) of 61 in placebo. Four (6.6%) of
61 subjects in a maintenance placebo condition left the study against
medical advice, compared with 1 (1.7%) of 58 taking nortriptyline. One
patient committed suicide 1 year after leaving the study against
medical advice.

COMMENT

To our knowledge, this is the first placebo-controlled study of
maintenance pharmacotherapy and psychotherapy in old-age depression.
The data confirm our hypothesis that maintenance nortriptyline and IPT,
together and singly, would be superior to medication clinic visits and
no pharmacotherapy in preventing or delaying recurrence of major
depressive episodes. In addition, we observed a clinically significant
effect for combined treatment over monotherapy in the prevention of
recurrence. This effect was clearest during the first year of
maintenance treatment, when most recurrences took place, especially in
patients 70 years or older. The current data extend the observations of
Frank et al19 into old age, replicating
their findings in
midlife patients with recurrent depression for the superior maintenance
efficacy of a TCA (imipramine) and IPT. However, one important
difference in outcomes is that the current study suggests a clinically
significant advantage of combined medication and psychotherapy over
medication alone in the elderly, an advantage not apparent in the
midlife study. The late-life data also support the concept of increased
liability to recurrence as a function of older age at study entry, as
evidenced especially by the brittle response of subjects aged 70 years
or older during the first year of maintenance treatment. We did not
detect a significant effect of chronic medical burden or time to
remission on the liability to recurrence.

Two published studies have supported the efficacy of continuation or
maintenance pharmacotherapy for preventing recurrences of major
depression in the elderly. Georgotas et al34 reported
relapse rates of 17% for nortriptyline and 20% for phenelzine sulfate
in elderly depressed patients during 4 to 8 months of continuation
therapy. The Old Age Depression Interest Group in the United
Kingdom35 reported that elderly patients with major
depression are 2.5 times less likely to suffer recurrence of major
depression while taking dothiepin hydrochloride maintenance (75 mg/d
for 2 years) than taking placebo. In a subsequent placebo-controlled
comparison of nortriptyline and phenelzine in 1-year maintenance
therapy, Georgotas et al36 reported that "patients
administered phenelzine (n=15) did significantly better
with 13.3% recurrences than patients administered either nortriptyline
(n=13; 53.8% recurrences) or placebo
(n=23, 65.2% recurrences)." It is important to note
that the nortriptyline window used in the study by Georgotas et
al36 was 50 to 170 ng/mL, which is
outside the recognized therapeutic range.

Although the applicability of the current findings to patients seen by
primary care or other nonpsychiatric physicians is unclear, patients
such as those in our study are now more likely to be seen in general
practice settings, since the managed care revolution. Similarly, a
substantial proportion of older patients (at least 119 of the 687
screened for this study) experience a first episode of depression in
later life. Although treatment for these patients was not addressed in
this study, recent data from
Flint and Rifat37 suggest that
such patients also have a high liability for recurrence even after 2
years of successful maintenance pharmacotherapy. What are the
implications, then, of the current study for general medical practice?

We suggest that the continuation of combined medication and
psychotherapy may represent the best long-term treatment strategy for
preserving recovery in elderly patients with recurrent major
depression. The clinical characteristics of elderly patients may
provide clues as to why combined treatment is an effective strategy for
maintaining wellness in the face of high liability to recurrence of
depression. Elderly depressed patients, whether in primary care or
psychiatric practice, are often characterized by high levels of
medical comorbidity, impaired subjective sleep quality, and frequently
occurring issues of bereavement, role transition, and interpersonal
conflict. High levels of chronic medical burden, impaired sleep
quality, and depletion of psychosocial resources highlight the
challenge of getting such patients well and keeping them free of
depression. In other words, the clinical context of major depression in
later life is complex both medically and
psychosocially, contributing to the increase in
observed brittleness of long-term response, especially after age 70
years.15 A combined
treatment approach may be best suited
for dealing with both the biological and psychosocial substrates of
old-age depression. It may also encourage better compliance with
pharmacotherapy. Hence, we recommend that all older patients with
recurrent depression be referred for psychotherapy, even if the
pharmacotherapy is managed by the primary care physician.

More data are needed from studies of patients 70 years or
older, as emphasized by a recent update of the NIH Consensus
Development Conference on late-life depression.38 Moreover, although nortriptyline is still useful, clinical practice, particularly
in primary care settings, has evolved during the past decade from TCAs
to selective serotonin reuptake inhibitors. Many physicians are
disinclined to prescribe TCAs to elderly patients. Thus, controlled
assessment of the maintenance efficacy of the serotonin reuptake
inhibitors in the elderly is needed, since no such data exist. More
heterogeneous study populations, including patients with a broader
range of cognitive impairment and medical illness, would serve to
enhance the generalizability of findings regarding long-term treatment
strategies in old-age depression. Aside from generalizability issues,
however, decisions about treatment choices must depend not only on
effectiveness but also on relative costs. We hypothesize that the
continuation of combined medication and psychotherapy would represent
the most effective long-term treatment strategy in such patients and
that the cost-effectiveness ratio would favor the use of combined
treatment over monotherapy. As emphasized by the World Health
Organization report on the global burden of disability,9 finding ways of keeping older patients depression-free needs to become
a high public health priority to meet the challenges posed by
demographic shifts that will occur in the next 10 to 15 years.

Old Age Depression Interest Group (OADIG). How long
should the elderly take antidepressants? a double-blind,
placebo-controlled study of continuation/prophylaxis therapy with
dothiepin. Br J Psychiatry.1993;162:175-182.